FGFR3
FGFR3 '(Fibroblast Growth Factor Receptor 3) is a member of a highly evolutionary conserved family of fibroblast growth factor receptors 1. The FGFR receptors are tyrosine kinases spanning the cellular membrane, which are activated by binding of ligands of the FGF family of growth factors. They consist of three extracellular immunoglobulin-like domains of a membrane spanning domain and of two intracellular tyrosine kinase domains transmitting a mitogenic signal. Extracellular FGF ligands activate FGFR signaling via formation of FGFR dimers. This dimer formation requires the assistance of heparin sulfate proteoglycans. 'The FGFR3 gene The human FGFR3''gene is present on chromosome 4 and has approximately 15565 bps 6. It has nine transcripts, containing 36 exons on the forward strand. FGFR3 contains 488SNPs and has 62 orthologues and 1 paralog . It is regulated by 9 regulatory elements. FGFR3 is mainly expressed in kidney, lung, brain, intestine, pancreas, testis and cartilage cells 4. click here to find more about the gene information in the EBI database, and to this link to search in NCBI database. The entire sequence of the FGFR3 gene can be found in ENSEMBLE at this link or in FASTA format here . As mentioned above the human FGFR3 gene has 62 orthologues. Most of them are present in placental mammals, especially in primates and rodents. The tree of human FGFR3 gene orthologues can be graphically displayed by clicking on this link or in the slideshow above. 'The FGFR signaling pathway' There are two isoforms of FGFR3 - IIIb and IIIc. As their name suggests, they are generated by a process known as alternative splicing in their third imunoglubuline-like domain of the receptor4. While the FGFR3 IIIc isoform is expressed mainly in chondrocytes, the IIIb form is present mostly in epithelial cells. Activation of the FGFR is triggered by binding of lingands of the FGF family and mediated by low-affinity FGF receptors - sulphated glycosaminoglycans (f.e. heparin, heparan). But isoforms of FGFR3 (IIIb and IIIc) are activated by FGF1 and FGF9 ligands. In addition, FGFs 2, 4, 6, and FGF8 also bind to FGFR3 IIIc. Ligand binding triggers FGF receptor dimerisation and autophosphorylation of the receptor tyrosine kinase residues. This uncovers domains for SH2 (Src-homology 2) and PTB (phosphotyrosine binding sites) of signalling proteins. A key protein of FGFR3 signalling is FRS2 (Fibroblast growth factor receptor substrate 2), by which the FGF receptors regulate the PI-3K and the Ras/MAPK pathways 5 . The phosphorylation of FRS2 allows the recruitment of adaptor proteins such as SOS (son of sevenless) and GRB2 (Growth factor receptor bound 2), which then activates RAS and downstream RAF and MAPK pathways. The PI-3K pathway is activated by a different complex formation. This complex involves GAB1 (GRB2-associated binding protein 1). Induction of PI-3K leads to activation of a AKT-dependent anti-apoptotical pathway. Another important kinase, which binds to the FGF receptor directly is Phospholipase γ (PLCγ)'.' Activated PLCγ hydrolyzes phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5- triphosphate (PIP3) and diacylglycerol (DAG) activating protein kinase C (PKC) increases phosphorylation of the MAPK pathway. 'FGFR3 function and association with human diseases' '''FGFR3 and skeletal dysplasias:' In humans FGFR3 protein is encoded by the FGFR3 gene and it is a physiological regulator of skeletal growth 2. It limitates the growth of long bones by inhibiting proliferation of chondrocytes. Therefore, defects in this gene are related to five skeletal dysplasias 3: *achondroplasia (ACH)/ hypochondroplasia (HCH) *thanatophoric dysplasia (TD) *acanthosis nigricans (SADDAN) *platyspondylic lethal skeletal dysplasia Achondroplasia: ACH may be inherited as an autosomal dominant trait, therefore people with ACH have one normal copy of the FGFR3 gene and one mutant copy. Two mutant copies of the FGFR3 genes are lethal. This means that a person with achondroplasia has a 50% chance of passing this disease to his offspring. ACH is characterized by a short statue with bowed legs, an abnormal hand appearance, decreased muscle tone and a large head. A milder form of ACH is hypochondroplasia (HCH). SADDAN dysplasia has also similar symptoms as ACH, but they are usually much more severe (including profound developmental delay and brain structure alteration). FGFR3 mutations and cancer: FGFR3 is one of the most commonly mutated genes in human urothelial cell carcinoma (UCC) 7. FGFR3 mutation has also been identified in cancer types such as cervical cancer, prostate cancer and spermatocytic seminomas. Lately, a lot of attention was paid to FGFR3 mutations, which were not only observed in Achondroplasia but also in multiple myeloma (especially due to translocation t(4;14), which results in ectopic expression of FGFR3)4. Therefore FGFR3 can act as an oncogene. FGFR receptors become oncogenic by several ways 7: *by chromosomal translocations which lead to expression of fusion proteins with oncogenic functions *due to FGFR overexpression and amplification *by poin mutations and single-nucleotide polymorphisms *alternative splicing *impaired termination of signalling *Increased autocrine or paracrine ligand stimulation of cancer growth reference: 1 Eswarakumar V.P., Lax I and Schlessinger J., Cellular Signaling by fibroblast growth factor receptors, Cytokine and Growth Factor Reviews, 16 '''139-149, 2005 2 Deng Ch., Wynshaw-Boris A., Zhou F., Kuo A. and Leder P., '''Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth, Cell, 84 911-921, 1996 3 Foldynova-Trantirkova S., Wilcox W. R., Krejci P., Sixteen Years and Counting: The Current Understanding of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling in Skeletal Dysplasias, Human mutation, 33 '''29-41, 2011 4 L'Hote C.G.M. and Knowles M. A., '''Cell responses to FGFR3 signalling: growth, differentiation and apoptosis, Experimental Cell Research, 304 417-431, 2005 5 Turner N. and Grose R., Fibroblast Growth Factor Signalling: from development to cancer, Nature reviews, 10 '''116-129, 2010 6 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002544/ 7 Ahmad I., Iwata T. and Leung H.Y., '''Mechanisms of FGFR-mediated carcinogenesis, Biochimica and Biophysica Acta, 1823, 850-860 (2012)